**13. Discussion**

### **13.1. Aspects of MRI imaging before CAS**

The MRI scan before CAS showed great variety in the changes in the 36 patients, with special attention to ischemic aspects. We found four (11.1%) patients with hypersignal foci (a total of six foci) in the DWI MRI before CAS. These foci are considered recent ischemia foci, and they are not reported as NF involved with CAS, although most remained after treatment. This rate is similar to that reported by Jaeger et al. [56] In a study involving 70 CAS, the authors discovered hypersignal lesions in diffusion before CAS in 10 (14%) of the patients, with a total of 24 foci [56]. Images of ischemia in DWI were detected in 10 (19%) patients before CAS by Hammer et al. [61]. Hammer et al. [61] suggested that recent ischemia foci presented by some patients on the initial MRI indicate the relevance of performing an MRI scan before CAS to guarantee that any foci in the MRI after CAS are related to the procedure.

Piñero et al. [48] found lesions in the DWI ipsilateral to the carotid artery undergoing CAS in 11% of the patients. In our data, 88.33% of the lesions found in the DWI before the CAS were ipsilateral to the carotid artery treated. This result supports the idea that these plaques are constantly forming emboli that can be sent to the brain.

Our data showed that carotid atherosclerotic plaques are probable causes of hypersignal lesions in DWI before CAS and can be considered causes of ischemia symptoms. This finding is corroborated by the fact that most patients were symptomatic (75.0%). Most of the patients (63.9%) showed old cerebral infarcts in the T2 sequence of the MRI before CAS. In our series, a strong correlation between the rates of old infarcts and positive symptoms was found (75.0%).

#### **13.2. Diffusion MRI study after CAS**

According to Bates et al. [13], while the primary purpose of revascularizing the carotid artery is preventing cerebral infarction, current treatments, both CAS and endarterectomy, carry a risk of triggering brain infarction.

All interventional procedures performed in craniofacial vascular regions carry an inherent risk of causing embolisms to the brain with different levels of severity. In these cases, the diffusion MRI technique is the most efficient tool for detecting acute focal cerebral ischemia [46,71,72].

Angioplasty is certainly the interventional procedure in the craniofacial region that carries the greatest risk of embolism. This risk is well documented in various studies and varies greatly among the different groups that it effects [35,37,73].

The institution wherein the present study was conducted published data pertaining to 1,037 carotid angioplasties with stent implantation and cerebral protection in 2006. The incidence of disabling neurological complications and death was 2.2% [38]. Despite the low morbi-mortality of the method, the real incidence of embolism is not known because the patients remained asymptomatic.

In summary, our DWI MRI study after CAS found that 50.00% of patients showed NF of restriction/ischemia in DWI after CAS. All of the NF were clinically silent (100%). These NF were located in a cerebral area fed by the cerebral artery subjected to CAS in 77.19% of patients and an area smaller than 10 mm in 91.53% of patients. The NF in cerebral areas not fed by the cerebral artery undergoing angioplasty corresponded to 22.81% of NFs. The presence of

The MRI scan before CAS showed great variety in the changes in the 36 patients, with special attention to ischemic aspects. We found four (11.1%) patients with hypersignal foci (a total of six foci) in the DWI MRI before CAS. These foci are considered recent ischemia foci, and they are not reported as NF involved with CAS, although most remained after treatment. This rate is similar to that reported by Jaeger et al. [56] In a study involving 70 CAS, the authors discovered hypersignal lesions in diffusion before CAS in 10 (14%) of the patients, with a total of 24 foci [56]. Images of ischemia in DWI were detected in 10 (19%) patients before CAS by Hammer et al. [61]. Hammer et al. [61] suggested that recent ischemia foci presented by some patients on the initial MRI indicate the relevance of performing an MRI scan before CAS to

Piñero et al. [48] found lesions in the DWI ipsilateral to the carotid artery undergoing CAS in 11% of the patients. In our data, 88.33% of the lesions found in the DWI before the CAS were ipsilateral to the carotid artery treated. This result supports the idea that these plaques are

Our data showed that carotid atherosclerotic plaques are probable causes of hypersignal lesions in DWI before CAS and can be considered causes of ischemia symptoms. This finding is corroborated by the fact that most patients were symptomatic (75.0%). Most of the patients (63.9%) showed old cerebral infarcts in the T2 sequence of the MRI before CAS. In our series, a strong correlation between the rates of old infarcts and positive symptoms was found (75.0%).

According to Bates et al. [13], while the primary purpose of revascularizing the carotid artery is preventing cerebral infarction, current treatments, both CAS and endarterectomy, carry a

All interventional procedures performed in craniofacial vascular regions carry an inherent risk of causing embolisms to the brain with different levels of severity. In these cases, the diffusion MRI technique is the most efficient tool for detecting acute focal cerebral ischemia [46,71,72]. Angioplasty is certainly the interventional procedure in the craniofacial region that carries the greatest risk of embolism. This risk is well documented in various studies and varies greatly

previous cerebral infarcts on the MRI influenced the appearance of NF (p=0.037).

guarantee that any foci in the MRI after CAS are related to the procedure.

constantly forming emboli that can be sent to the brain.

among the different groups that it effects [35,37,73].

**13.2. Diffusion MRI study after CAS**

risk of triggering brain infarction.

**13. Discussion**

**13.1. Aspects of MRI imaging before CAS**

176 Carotid Artery Disease - From Bench to Bedside and Beyond

We found restriction foci in the diffusion MRIs of 18 of the 36 (50%) patients in our series. These NF in the DWI after CAS are additional to those in the first MRI, which implies that the procedure or some aspect of it is related to the appearance of NF. The fact that all of the patients in this series were asymptomatic after CAS and remained so during the intrahospital obser‐ vation period should also be taken into account.

The percentage of patients with NF in DWI in similar studies is quite variable: 9 to 78% (9% [74]; 15.8% [71]; 17.3% [48]; 20.4% [75]; 29% [56]; 30% [36]; 40% [61]; 41.5% [73]; 42% [46]; 42.6% [69]; 43% [59]; 49% [34]; 52% [35], 54% [58], 59.2% [76]; 9 and 78% [77]; 70% [70]).

The comparison of different studies is very difficult because even a small variation in the period after the CAS during which DWI was conducted might affect the result. In the study by Rapp et al. [77], a total of 23 patients underwent two MRI exams after the CAS. The first MRI scan was performed immediately after the procedure (1 to 2 h) and the second exam was performed 48 h later. The results indicated only two (9%) cases with NF in the DWI immediately after the procedure and 18 (78%) cases with NF 48 h later [77]. In a recent meta-analysis that included studies that followed the evolution of CAS by DWI (1,363 CAS), NF were found in 37% of patients [37].

The study that is most similar to ours is Kastrup et al. (2006); this study found microembolia in 49% of patients with cerebral protection. Two years later, the authors updated their series and published that NF occurred after CAS with a cerebral protection filter in 52% of patients [35].

du Mesnil de Rochemont et al. [46] found NF in 42% of CAS and, similar to our study, found no neurological deficit. In addition to this study, several others [35,37,48,61,69,73] have found that most patients remained asymptomatic after CAS, despite the presence of NF. These findings encouraged us to look for factors that lead to ischemic changes.

Jaeger et al. [56] demonstrated that smaller NF are less likely to become definitive lesions. His study showed that of the 59 restriction foci in the diffusion after CAS, only 17 (29%) were observed in the T2 sequence. They found that 17% of the lesions smaller than 5 mm in the DWI were visible in T2; 36% of the lesions in DWI between 5 and 10 mm were observed in T2, and 100% of the larger lesions (larger than 10 mm) were apparent in T2 [56]. As in Tedesco et al. [70], we considered the hypersignal images in T2 as already defined and permanent ischemia foci, unlike the lesions in DWI, which may be reversible.

In a series of 59 CASs, Jaeger et al. [56] found that 75% of NF were smaller than 5 mm; in the series by Piñero [48], the lesions were smaller than 5 mm in 57% of patients. However, in a series of 22 CASs in Roh et al. [78], all of the NF were smaller than 10 mm. In our study, small NF (<10 mm) corresponded to a large majority (91.53%) of the NF, while large NF (>10 mm) composed only 8.46% of the NF; this result shows that the eventual emboli caused by the procedure are small in size.

arch and the supra-aortic trunks and to the prevention of emboli formation beyond the

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When patients with NF in an area other than the carotid artery for angioplasty are excluded (i.e., emboli resulting from catheterization), our risk of cerebral embolism from angioplasty

du Mesnil de Rochemont et al. [46] found an average of one NF per patient in the ipsilateral area, while Jaeger et al. found that the average number of NF ipsilateral to the CAS was 2.6 per patient and that the average number of NF contralateral to the CAS was 1.2 per patient [56]. In our study, the average number of ipsilateral NF was 2.8 per patient, and the average number

The highest mean (6.33) NF per patient was for the presentation of ipsilateral and contralateral NF simultaneously. This finding justifies the idea that the initial angiography or the catheter‐ ization technique and the CAS are involved in the high average number of bilateral NF.

Our average number of NF per patient, which was higher than that reported by most authors, may reflect the fact that most (66.7%) of our cases underwent a broad diagnostic exam before the angioplasty. Thus, the hypothesis can be applied that, because most of the cases had bilateral NF, these NF were more likely related to the catheterization than to the angioplasty

Because of the risk of embolism during angiographic exams (diagnostic) and in interventional procedures such as CAS, we believe that the exams should be performed by certified and experienced neuroradiologists only. This statement is supported by other authors [71,79].

Moreover, modern noninvasive methods can be used with good reproducibility in some centers, allowing a definition of the anatomy, degree of stenosis, and intracranial circulation, which enables decisions about the CAS to be made without the use of a broad angiography

Several other authors [8,48,56,58,71,80-82] studied risk factors for the occurrence of athero‐ sclerotic disease and ICVA, including diabetes, hypertension, coronary artery disease, ischemic peripheral vascular disease, hypercholesterolemia, arrhythmia, previous ischemic stroke, previous TIA, vasculitis, and hemorrhagic cerebrovascular accident. Most authors did not find significant differences related to the appearance of hypersignal foci in DWI. Some

Clinical risk factors were not significant determinants of the formation of NF after CAS in our study. The only risk factor statistically proven to be involved in the creation of lesions in DWI after CAS was a radiological factor: old cerebral infarcts shown on MRI images, especially in

Our study found a tendency toward a greater number of NF in older patients (≥75 years) and those who underwent angioplasty of the left carotid artery. Hammer et al. [61] identified a tendency for NF to be found in patients with advanced age (>75 years); however, as in our

authors found some relevant factors, but those were not confirmed by other authors.

study, they failed to prove it statistically (p=0.1).

collateral circulation by the Willis polygon or other routes [61].

alone is reduced from 50.00% (18 patients) to 32.35% (11 patients).

of contralateral NF was 1.0 per patient.

itself.

T2W.

before the CAS.

According to several authors, some lesions in DWI after CAS also occur in vascular regions independent from the CAS and are most likely related to the catheterization procedure [35,37,61,73]. Our data showed that most (77.19%) of the NF occurred in the region of the carotid artery that underwent angioplasty. However, a significant difference was not observed between the side of the CAS and the contralateral side in relation to NF.

In the publication by Piñero et al. [48], 67.9% of the NF were in the vascular area compatible with the CAS. However, Hammer et al. [61] found a similar number by studying 53 carotid angioplasties: 60% of the NF were in an ipsilateral situation to CAS and 40% occurred in contralateral topography.

By studying carotid angioplasty, Poppert et al. [58found NF in DWI in area of contralateral carotid or vertebral artery in 9.7% of patients. Poppert et al. [58] stated that during catheteri‐ zation, to reach the right internal carotid artery, the materials must pass the aortic arch at the origin of other cerebral arterial trunks, such as the common carotid artery and left subclavian artery, in addition to the brachiocephalic trunk next to the right vertebral artery. Thus, material from plaques along this route can cause emboli in various brain regions beyond the area nourished by the carotid artery undergoing CAS [58].

Maleux et al. [73] described their surprise at finding that 35.3% of the NF (26.3% in contralateral anterior circulation and 9% in the cerebellum) occurred in regions not nourished by the carotid artery ipsilateral to the CAS. They considered the manipulation of the guide wire, catheter, or guide catheter in the aortic arch as a possible cause of the lesions [73].

A meta-analysis with data collected from CAS studies between 2000 and 2007 found lesions in diffusion in 14.5% of CAS outside the region treated, and NF were observed in 35% of the procedures in the region of the carotid artery treated by CAS [37]. Thus, catheterization was one of the main causes of the microemboli.

In our study, half of the patients with NF had a single lesion (single NF), and the other half showed multiple foci (varying from 2 to 11 NF), which totaled 50 NF. Thus, patients with multiple NF accounted for 84.75% of the NFs found in diffusion. Our study reproduced the finding of Piñero et al. [48]. These studies found a single focus in DWI in 53.6% of patients, and multiple foci were found in 46.4% of the patients in diffusion after CAS [48].

In our study, we found five patients who showed ipsilateral NF, five patients who showed contralateral NF, and another six who showed ipsilateral and contralateral NF simultaneously. Thus, the ipsilateral situation was the main localization of the NF occurrence in absolute terms, but the most common presentation was associated to the contralateral NF than isolated. A similar distribution of laterality was found in a retrospective study by Tedesco et al. [70] of 27 CAS. Similar numbers were also observed by Hammer et al. [61], who, in a series of CAS under cerebral protection, found eight cases with only ipsilateral NF, seven cases with exclusively contralateral NF, and six cases with a combination of ipsilateral and contralateral NF. Accord‐ ing to these authors, these events can be related to the doctor's skill in catheterizing the aortic arch and the supra-aortic trunks and to the prevention of emboli formation beyond the collateral circulation by the Willis polygon or other routes [61].

composed only 8.46% of the NF; this result shows that the eventual emboli caused by the

According to several authors, some lesions in DWI after CAS also occur in vascular regions independent from the CAS and are most likely related to the catheterization procedure [35,37,61,73]. Our data showed that most (77.19%) of the NF occurred in the region of the carotid artery that underwent angioplasty. However, a significant difference was not observed

In the publication by Piñero et al. [48], 67.9% of the NF were in the vascular area compatible with the CAS. However, Hammer et al. [61] found a similar number by studying 53 carotid angioplasties: 60% of the NF were in an ipsilateral situation to CAS and 40% occurred in

By studying carotid angioplasty, Poppert et al. [58found NF in DWI in area of contralateral carotid or vertebral artery in 9.7% of patients. Poppert et al. [58] stated that during catheteri‐ zation, to reach the right internal carotid artery, the materials must pass the aortic arch at the origin of other cerebral arterial trunks, such as the common carotid artery and left subclavian artery, in addition to the brachiocephalic trunk next to the right vertebral artery. Thus, material from plaques along this route can cause emboli in various brain regions beyond the area

Maleux et al. [73] described their surprise at finding that 35.3% of the NF (26.3% in contralateral anterior circulation and 9% in the cerebellum) occurred in regions not nourished by the carotid artery ipsilateral to the CAS. They considered the manipulation of the guide wire, catheter, or

A meta-analysis with data collected from CAS studies between 2000 and 2007 found lesions in diffusion in 14.5% of CAS outside the region treated, and NF were observed in 35% of the procedures in the region of the carotid artery treated by CAS [37]. Thus, catheterization was

In our study, half of the patients with NF had a single lesion (single NF), and the other half showed multiple foci (varying from 2 to 11 NF), which totaled 50 NF. Thus, patients with multiple NF accounted for 84.75% of the NFs found in diffusion. Our study reproduced the finding of Piñero et al. [48]. These studies found a single focus in DWI in 53.6% of patients,

In our study, we found five patients who showed ipsilateral NF, five patients who showed contralateral NF, and another six who showed ipsilateral and contralateral NF simultaneously. Thus, the ipsilateral situation was the main localization of the NF occurrence in absolute terms, but the most common presentation was associated to the contralateral NF than isolated. A similar distribution of laterality was found in a retrospective study by Tedesco et al. [70] of 27 CAS. Similar numbers were also observed by Hammer et al. [61], who, in a series of CAS under cerebral protection, found eight cases with only ipsilateral NF, seven cases with exclusively contralateral NF, and six cases with a combination of ipsilateral and contralateral NF. Accord‐ ing to these authors, these events can be related to the doctor's skill in catheterizing the aortic

and multiple foci were found in 46.4% of the patients in diffusion after CAS [48].

between the side of the CAS and the contralateral side in relation to NF.

nourished by the carotid artery undergoing CAS [58].

one of the main causes of the microemboli.

guide catheter in the aortic arch as a possible cause of the lesions [73].

procedure are small in size.

178 Carotid Artery Disease - From Bench to Bedside and Beyond

contralateral topography.

When patients with NF in an area other than the carotid artery for angioplasty are excluded (i.e., emboli resulting from catheterization), our risk of cerebral embolism from angioplasty alone is reduced from 50.00% (18 patients) to 32.35% (11 patients).

du Mesnil de Rochemont et al. [46] found an average of one NF per patient in the ipsilateral area, while Jaeger et al. found that the average number of NF ipsilateral to the CAS was 2.6 per patient and that the average number of NF contralateral to the CAS was 1.2 per patient [56]. In our study, the average number of ipsilateral NF was 2.8 per patient, and the average number of contralateral NF was 1.0 per patient.

The highest mean (6.33) NF per patient was for the presentation of ipsilateral and contralateral NF simultaneously. This finding justifies the idea that the initial angiography or the catheter‐ ization technique and the CAS are involved in the high average number of bilateral NF.

Our average number of NF per patient, which was higher than that reported by most authors, may reflect the fact that most (66.7%) of our cases underwent a broad diagnostic exam before the angioplasty. Thus, the hypothesis can be applied that, because most of the cases had bilateral NF, these NF were more likely related to the catheterization than to the angioplasty itself.

Because of the risk of embolism during angiographic exams (diagnostic) and in interventional procedures such as CAS, we believe that the exams should be performed by certified and experienced neuroradiologists only. This statement is supported by other authors [71,79].

Moreover, modern noninvasive methods can be used with good reproducibility in some centers, allowing a definition of the anatomy, degree of stenosis, and intracranial circulation, which enables decisions about the CAS to be made without the use of a broad angiography before the CAS.

Several other authors [8,48,56,58,71,80-82] studied risk factors for the occurrence of athero‐ sclerotic disease and ICVA, including diabetes, hypertension, coronary artery disease, ischemic peripheral vascular disease, hypercholesterolemia, arrhythmia, previous ischemic stroke, previous TIA, vasculitis, and hemorrhagic cerebrovascular accident. Most authors did not find significant differences related to the appearance of hypersignal foci in DWI. Some authors found some relevant factors, but those were not confirmed by other authors.

Clinical risk factors were not significant determinants of the formation of NF after CAS in our study. The only risk factor statistically proven to be involved in the creation of lesions in DWI after CAS was a radiological factor: old cerebral infarcts shown on MRI images, especially in T2W.

Our study found a tendency toward a greater number of NF in older patients (≥75 years) and those who underwent angioplasty of the left carotid artery. Hammer et al. [61] identified a tendency for NF to be found in patients with advanced age (>75 years); however, as in our study, they failed to prove it statistically (p=0.1).

du Mesnil de Rochemont et al. [46] confirmed this trend by finding that age above 70 years old was a predictor for the occurrence of foci in diffusion, and they wondered whether this finding could be related to the fact that more elderly patients have more diffuse atherosclerosis compared with younger patients. These authors did not find a significant correlation for factors such as gender, degree of stenosis, type of stent, type of filter, and risk factors, such as hypertension, diabetes, smoking, hypercholesterolemia, coronary heart disease, and periph‐ eral arterial occlusive disease [46].

This association makes it clear that a definitive ischemic lesion in imaging (in T2W) is a great risk factor for developing microembolic complications during carotid angioplasty. Thus, the patients who have infarcts caused by embolism or other factors are the same patients who present NF after CAS. Additionally, the tendency for symptomatic patients (who do not necessarily always present infarcts on MRI) to exhibit more NF after CAS indicates that the main cause of microemboli during CAS may be the patients' condition, including the plaque composition, risk factors, and how the atherosclerosis presents in their bodies. It is possible that the NF are signs of the underlying disease, and they may be exacerbated during CAS. Our idea about the vulnerability of plaque is shared by Piñero at al. [71], who evaluated the composition of the material found in the filters after CAS and stated that the atheromatous

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Despite several publications on signs compatible with microemboli after CAS and CEA, no consensus can be found among authors regarding the real clinical representation of NF. According to some authors [62,69], the clinical value of NF after CAS is not adequately clear. In our study, although 50% of patients showed foci compatible with ischemia in the diffusion after angioplasty, none showed ischemic neurological syndrome. Some published series have obtained a similar result, meaning most patients with NF after CAS were asymptomatic [46,54]. While the brain shows some tolerance for microemboli [83,84], the fact that subclinical deficits promoted in the NF areas after CAS may cause long-term neurological deterioration cannot

The clinical impact of these clinically "silent" lesions in the brain that do not cause motor, sensory, or linguistic deficits (i.e., in non-eloquent brain areas) was debated by Bendszus [63, 80]. According to these authors, there is evidence that the cumulative load of ischemic brain

However, the discrepancy between the clinical safety of CAS and the number of NF of ischemia is intriguing. It is known that there can be TIA abnormalities in DWI that undergo regression and do not cause lesions that remain as ischemic scares in T2. Despite the normalization of DWI after TIA, structural damage caused by late neuronal apoptosis may be present, even in the absence of tissue necrosis [63]. For these authors, DWI shows the entire picture of emboli during different procedures, and the ischemic conditions are only

Studying the DWI sequence in patients with clinical conditions of TIA, Kidwell et al. showed that in five of nine patients with ischemia foci in DWI after TIA, no evidence of infarcts was found in follow-up imaging scans, indicating that almost half of the lesions from DWI in TIA may be completely reversible on imaging [85]. Thus, we most likely overestimate the true

Although not part of research protocol, an MRI scan was conducted 40 days after CAS in a patient who showed NF in the MRI after CAS. The third MRI scan did not show ischemic lesions in the DWI or in T2. Thus, the NF indicated in the MRI after CAS proved evanescent (like short-lived). This suggests that small lesions in the DWI that occur after CAS and are

incidence of cerebral ischemic lesion after CAS when we base it only on DWI of MRI.

plaque and the vessel wall are the main sources of microemboli during CAS.

be neglected. Long-term studies on cognitive function are needed.

the visible tip of the iceberg [63].

clinically silent may not be definitive ischemic lesions.

injury can cause neuropsychological deficits or aggravate vascular dementia.

Generally, our group without NF showed fewer risk factors (56 factors) than the group with NF after CAS did (60 factors). While not significant, the difference shows a tendency that the more comorbidities the patient has, the greater his or her risk of developing NF in a CAS. The difference was also not significant for the clinical conditions of previous ischemic cerebrovas‐ cular accident and transient ischemia attack. Similarly, for the risk factor of cerebral ischemia, which was associated with both TIA and ICVA, the difference was also not significant.

In our group (n=36), which was characterized by advanced age (average of 72 years), serious stenosis (average narrowing of 76.31%) and symptoms of previous ischemic conditions in most patients (72.22%), the subgroup of previously asymptomatic patients showed a lower risk of NF: only 18.6% of the observed NF. Moreover, a large majority, 48/59 (81.4%) of the NF occurred in symptomatic patients. Despite this tendency, there was not a significant difference. Hammer et al. [61], in a series of 53 CAS, identified a tendency to find NF in symptomatic patients, although no statistical proof was found.

According to Kastrup et al. [35], it is conceivable that the high prevalence of active plaques with thrombotic activity in recently symptomatic patients may determine the high rate of NF in this group. When our patients are regrouped into asymptomatic (9 patients) and sympto‐ matic (27 patients) groups to evaluate the interference of previous symptoms with the occurrence of NF, the hypothesis is confirmed. The asymptomatic patients did not develop NF in most (77.8%) of the CAS cases, while the symptomatic patients showed NF in most cases (59.3%). Again, the analysis did not prove a significant difference (p=0.121), but it confirms the tendency for symptomatic patients to be at greater risk in the procedure. Piñero et al. [48] also showed an increased risk of embolism in angioplasty for symptomatic patients in their series (19.8%) compared to asymptomatic patients (10%; p = 0.155). This ratio is approximately 2:1, while ours was approximately 2.7:1.

We found a significant difference in the NF lesions in DWI after CAS in patients with previous infarcts (based on the T2 sequence) compared with those without. Cerebral infarct was present in 63.9% of patients in our entire series. It was observed that most (83.3%) of the patients with NF after CAS showed cerebral infarcts on the MRI before the CAS. Nonetheless, the patients who did not show cerebral infarcts on the MRI before the CAS mostly evolved (55.6%) without NF in the DWI after CAS (p=0.037). Again, the average number of NF varies enormously in relation to whether the patient had or not a previous infarct on T2 (initial MRI). The average NF in the group with a previous cerebral infarct was 2.43 NF/patient, while the average in the group without a previous infarct was only 0.23 NF/patient (p=0.011).

This association makes it clear that a definitive ischemic lesion in imaging (in T2W) is a great risk factor for developing microembolic complications during carotid angioplasty. Thus, the patients who have infarcts caused by embolism or other factors are the same patients who present NF after CAS. Additionally, the tendency for symptomatic patients (who do not necessarily always present infarcts on MRI) to exhibit more NF after CAS indicates that the main cause of microemboli during CAS may be the patients' condition, including the plaque composition, risk factors, and how the atherosclerosis presents in their bodies. It is possible that the NF are signs of the underlying disease, and they may be exacerbated during CAS. Our idea about the vulnerability of plaque is shared by Piñero at al. [71], who evaluated the composition of the material found in the filters after CAS and stated that the atheromatous plaque and the vessel wall are the main sources of microemboli during CAS.

du Mesnil de Rochemont et al. [46] confirmed this trend by finding that age above 70 years old was a predictor for the occurrence of foci in diffusion, and they wondered whether this finding could be related to the fact that more elderly patients have more diffuse atherosclerosis compared with younger patients. These authors did not find a significant correlation for factors such as gender, degree of stenosis, type of stent, type of filter, and risk factors, such as hypertension, diabetes, smoking, hypercholesterolemia, coronary heart disease, and periph‐

Generally, our group without NF showed fewer risk factors (56 factors) than the group with NF after CAS did (60 factors). While not significant, the difference shows a tendency that the more comorbidities the patient has, the greater his or her risk of developing NF in a CAS. The difference was also not significant for the clinical conditions of previous ischemic cerebrovas‐ cular accident and transient ischemia attack. Similarly, for the risk factor of cerebral ischemia, which was associated with both TIA and ICVA, the difference was also not significant.

In our group (n=36), which was characterized by advanced age (average of 72 years), serious stenosis (average narrowing of 76.31%) and symptoms of previous ischemic conditions in most patients (72.22%), the subgroup of previously asymptomatic patients showed a lower risk of NF: only 18.6% of the observed NF. Moreover, a large majority, 48/59 (81.4%) of the NF occurred in symptomatic patients. Despite this tendency, there was not a significant difference. Hammer et al. [61], in a series of 53 CAS, identified a tendency to find NF in symptomatic

According to Kastrup et al. [35], it is conceivable that the high prevalence of active plaques with thrombotic activity in recently symptomatic patients may determine the high rate of NF in this group. When our patients are regrouped into asymptomatic (9 patients) and sympto‐ matic (27 patients) groups to evaluate the interference of previous symptoms with the occurrence of NF, the hypothesis is confirmed. The asymptomatic patients did not develop NF in most (77.8%) of the CAS cases, while the symptomatic patients showed NF in most cases (59.3%). Again, the analysis did not prove a significant difference (p=0.121), but it confirms the tendency for symptomatic patients to be at greater risk in the procedure. Piñero et al. [48] also showed an increased risk of embolism in angioplasty for symptomatic patients in their series (19.8%) compared to asymptomatic patients (10%; p = 0.155). This ratio is approximately 2:1,

We found a significant difference in the NF lesions in DWI after CAS in patients with previous infarcts (based on the T2 sequence) compared with those without. Cerebral infarct was present in 63.9% of patients in our entire series. It was observed that most (83.3%) of the patients with NF after CAS showed cerebral infarcts on the MRI before the CAS. Nonetheless, the patients who did not show cerebral infarcts on the MRI before the CAS mostly evolved (55.6%) without NF in the DWI after CAS (p=0.037). Again, the average number of NF varies enormously in relation to whether the patient had or not a previous infarct on T2 (initial MRI). The average NF in the group with a previous cerebral infarct was 2.43 NF/patient, while the average in the

group without a previous infarct was only 0.23 NF/patient (p=0.011).

eral arterial occlusive disease [46].

180 Carotid Artery Disease - From Bench to Bedside and Beyond

patients, although no statistical proof was found.

while ours was approximately 2.7:1.

Despite several publications on signs compatible with microemboli after CAS and CEA, no consensus can be found among authors regarding the real clinical representation of NF. According to some authors [62,69], the clinical value of NF after CAS is not adequately clear. In our study, although 50% of patients showed foci compatible with ischemia in the diffusion after angioplasty, none showed ischemic neurological syndrome. Some published series have obtained a similar result, meaning most patients with NF after CAS were asymptomatic [46,54].

While the brain shows some tolerance for microemboli [83,84], the fact that subclinical deficits promoted in the NF areas after CAS may cause long-term neurological deterioration cannot be neglected. Long-term studies on cognitive function are needed.

The clinical impact of these clinically "silent" lesions in the brain that do not cause motor, sensory, or linguistic deficits (i.e., in non-eloquent brain areas) was debated by Bendszus [63, 80]. According to these authors, there is evidence that the cumulative load of ischemic brain injury can cause neuropsychological deficits or aggravate vascular dementia.

However, the discrepancy between the clinical safety of CAS and the number of NF of ischemia is intriguing. It is known that there can be TIA abnormalities in DWI that undergo regression and do not cause lesions that remain as ischemic scares in T2. Despite the normalization of DWI after TIA, structural damage caused by late neuronal apoptosis may be present, even in the absence of tissue necrosis [63]. For these authors, DWI shows the entire picture of emboli during different procedures, and the ischemic conditions are only the visible tip of the iceberg [63].

Studying the DWI sequence in patients with clinical conditions of TIA, Kidwell et al. showed that in five of nine patients with ischemia foci in DWI after TIA, no evidence of infarcts was found in follow-up imaging scans, indicating that almost half of the lesions from DWI in TIA may be completely reversible on imaging [85]. Thus, we most likely overestimate the true incidence of cerebral ischemic lesion after CAS when we base it only on DWI of MRI.

Although not part of research protocol, an MRI scan was conducted 40 days after CAS in a patient who showed NF in the MRI after CAS. The third MRI scan did not show ischemic lesions in the DWI or in T2. Thus, the NF indicated in the MRI after CAS proved evanescent (like short-lived). This suggests that small lesions in the DWI that occur after CAS and are clinically silent may not be definitive ischemic lesions.

Similarly, a small study (seven patients) from Schlüter et al. [86] identified reversal on imaging in 76% (5/21) of the NF after CAS at an average MRI follow-up four months later. A recent study showed that 92.1% of the signs of microemboli disappeared and that 5.2% remained in an MRI study three months after the CAS [72]. Thus, the NF after CAS are potentially reversible on imaging and without neurological developments [60,75,86].

stenosis in groups of patients with and without NF after CAS. Schnaudigel et al. [37], in a metaanalysis, considered that the degree of stenosis influenced the incidence of NF after CAS; however, it was difficult to compare the articles because of great variation in the diagnostic methods (DSA, CTA, MRA, and Doppler) and methodologies (NASCET, ECST or not men‐ tioned) used to grade the stenosis [37]. Roh et al. [78] found NF after CAS in eight of 22 (36%) cases. Thus, similar to us, they did not find a significant difference in the presence of NF in relation to the presence or absence of ulcers in the plaque. Among our patients, the percentages

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We note that ulcers did not influence the result of embolism, although one of the steps, overcoming the ulcerated stenosis by the still-closed closed filter, occurred without cerebral protection. This fact may suggest the safety of filters in crossing stenotic lesions, even ana‐ tomically complex ones, such as ulcerated plaques. More studies are needed to prove this hypothesis. Lacroix et al. [69], in a series of 61 CASs, analyzed technical conditions such as the procedure duration and presence of ulcers in atheromatous plaque. They did not find a

We did not find a significant difference between contralateral occlusion and the occur‐ rence of NF after CAS. This finding confirms the clinical reasoning that patients with carotid stenosis and contralateral carotid occlusion have an embolism risk similar to that of other patients during CAS treatment. This fact contrasts with endarterectomy, for which the clinical results are materially negatively influenced by the presence of contralateral carotid

The fluoroscopy time used in CAS may reflect the technical difficulty of the procedure as this time is equivalent to the set of short intervals in which X-ray was applied during the maneuvers necessary for the catheters, guides, balloons, stents, and other materials [82]. Pinheiro et al. [48] used fluoroscopy for 21 min (average) per CAS, a result similar to our series (22.93 min per CAS). As in our study, Tedesco et al. [70] did not find a correlation between long fluoroscopy times or greater amounts of contrast and the appearance of NF after CAS. Conversely, Rapp et al. [77] found an increase in NF after CAS depending on the fluoroscopy time used. However, the fact that we did not find a significant difference in the fluoroscopy time between the groups with and without embolism suggests that cases in which the angioplasty is technically difficult may require longer times for the interven‐ tionist, but theoretically, the increased time does not increase in the risks of embolism. The CASs in this study were always conducted by an individual with a considerable amount of experience. The only way to exclude this bias would be to evaluate the learning curve

Although each contrast injection has an unknown theoretical risk of carrying emboligenic particles, this was not proven in our series, but there was not a significant difference in volume between the groups with and without NF. Nonetheless, we remember that, in medical services such as ours with a neuroradiology practice, the cases of embolism are possibly not due to the technique used because the contrast volume and the fluoroscopy time are similar for both groups. Moreover, it is possible that the risk of embolism may be endogenous to patients at a neuroradiology institution where the iatrogenic embolism factor is studied and controlled. The

with ulcers were identical in the groups with and without embolism in CAS.

correlation between these elements and the frequency of NF in DWI.

of a technician in training, which may explain the results of [77].

occlusion [10,91-93].

Some authors [69,87] correlated the neurological deficits after CAS with the diameter of the foci of ischemia in the DWI. Small lesions were associated with good clinical evaluation. Small NF (>5 mm) were reported as having the highest chance of not becoming definitive ischemic lesions in later MRI scans compared with NF larger than 5 mm [75]. In addition to the size of the foci in DWI, the topography may also determine whether the lesion will be clinically silent or not [56,71].

For Piñero et al. [48], the position of the lesions in the diffusion was predominantly cortical and subcortical in 67.9%.The study by Jaeger et al. showed that 95% of the NF had a cortical/ subcortical localization, mainly in the area of the ACA and MCA. Jaeger et al. considered this distribution to be more compatible with standard cerebral embolism than with types of cerebral ischemia [56].

Similar to Piñero et al. [48] and Jaeger et al. [56], the predominant pattern of the NF in our study were lesions with small diameters and apparently random distribution. This finding is compatible with the topography of the distal arteries, including the cortical and subcortical vessels and perforating branches. There was also no predominance in border ("watershed") areas of vascularization.

Although we found NF in various areas, such as the motor cortex and basal ganglia, the patients presented no clinical deficit during the hospitalization period. It may be that because the NF had a small volume, they were less relevant for clinical lesions due to collateral circulation, despite being in eloquent area. Nonetheless, improvement in cerebral perfusion was shown after CAS in publications by Tavares and Caldas and may counterbalance clinical damage resulting from microemboli that occur after CAS [68,88,89].

#### **13.3. Aspects of angiography, angioplasty, and cerebral protection**

In addition to maintaining a constant flow to the brain in all phases of CAS, cerebral protection with a filter is likely to be used in all cases (unlike the occlusive balloon technique, which is reserved for patients who are candidates for temporary carotid occlusion) [42]. Other limita‐ tions of techniques that use balloon for cerebral protection include severe tortuosity of the cervical and thoracic arteries and increased diameter of the external carotid >6 mm [72]. These were our reasons for choosing filters as a means of protection in our cases.

Angiographic factors and factors in the angioplasty, such as percentage of stenosis, presence of ulceration in the plaque, and number of catheters used, did not show a statistically signifi‐ cant difference in our study with respect to the appearance of NF after CAS. In contrast to our findings, Ohki et al., studying ex vivo angioplasty with stent, found that the greatest number of particles during the procedure was associated with serious stenosis >90% [90]. Gauvrit et al. [74], similar to our findings, did not find a significant difference between the degree of stenosis in groups of patients with and without NF after CAS. Schnaudigel et al. [37], in a metaanalysis, considered that the degree of stenosis influenced the incidence of NF after CAS; however, it was difficult to compare the articles because of great variation in the diagnostic methods (DSA, CTA, MRA, and Doppler) and methodologies (NASCET, ECST or not men‐ tioned) used to grade the stenosis [37]. Roh et al. [78] found NF after CAS in eight of 22 (36%) cases. Thus, similar to us, they did not find a significant difference in the presence of NF in relation to the presence or absence of ulcers in the plaque. Among our patients, the percentages with ulcers were identical in the groups with and without embolism in CAS.

Similarly, a small study (seven patients) from Schlüter et al. [86] identified reversal on imaging in 76% (5/21) of the NF after CAS at an average MRI follow-up four months later. A recent study showed that 92.1% of the signs of microemboli disappeared and that 5.2% remained in an MRI study three months after the CAS [72]. Thus, the NF after CAS are potentially reversible

Some authors [69,87] correlated the neurological deficits after CAS with the diameter of the foci of ischemia in the DWI. Small lesions were associated with good clinical evaluation. Small NF (>5 mm) were reported as having the highest chance of not becoming definitive ischemic lesions in later MRI scans compared with NF larger than 5 mm [75]. In addition to the size of the foci in DWI, the topography may also determine whether the lesion will be clinically silent

For Piñero et al. [48], the position of the lesions in the diffusion was predominantly cortical and subcortical in 67.9%.The study by Jaeger et al. showed that 95% of the NF had a cortical/ subcortical localization, mainly in the area of the ACA and MCA. Jaeger et al. considered this distribution to be more compatible with standard cerebral embolism than with types of

Similar to Piñero et al. [48] and Jaeger et al. [56], the predominant pattern of the NF in our study were lesions with small diameters and apparently random distribution. This finding is compatible with the topography of the distal arteries, including the cortical and subcortical vessels and perforating branches. There was also no predominance in border ("watershed")

Although we found NF in various areas, such as the motor cortex and basal ganglia, the patients presented no clinical deficit during the hospitalization period. It may be that because the NF had a small volume, they were less relevant for clinical lesions due to collateral circulation, despite being in eloquent area. Nonetheless, improvement in cerebral perfusion was shown after CAS in publications by Tavares and Caldas and may counterbalance clinical

In addition to maintaining a constant flow to the brain in all phases of CAS, cerebral protection with a filter is likely to be used in all cases (unlike the occlusive balloon technique, which is reserved for patients who are candidates for temporary carotid occlusion) [42]. Other limita‐ tions of techniques that use balloon for cerebral protection include severe tortuosity of the cervical and thoracic arteries and increased diameter of the external carotid >6 mm [72]. These

Angiographic factors and factors in the angioplasty, such as percentage of stenosis, presence of ulceration in the plaque, and number of catheters used, did not show a statistically signifi‐ cant difference in our study with respect to the appearance of NF after CAS. In contrast to our findings, Ohki et al., studying ex vivo angioplasty with stent, found that the greatest number of particles during the procedure was associated with serious stenosis >90% [90]. Gauvrit et al. [74], similar to our findings, did not find a significant difference between the degree of

damage resulting from microemboli that occur after CAS [68,88,89].

**13.3. Aspects of angiography, angioplasty, and cerebral protection**

were our reasons for choosing filters as a means of protection in our cases.

on imaging and without neurological developments [60,75,86].

182 Carotid Artery Disease - From Bench to Bedside and Beyond

or not [56,71].

cerebral ischemia [56].

areas of vascularization.

We note that ulcers did not influence the result of embolism, although one of the steps, overcoming the ulcerated stenosis by the still-closed closed filter, occurred without cerebral protection. This fact may suggest the safety of filters in crossing stenotic lesions, even ana‐ tomically complex ones, such as ulcerated plaques. More studies are needed to prove this hypothesis. Lacroix et al. [69], in a series of 61 CASs, analyzed technical conditions such as the procedure duration and presence of ulcers in atheromatous plaque. They did not find a correlation between these elements and the frequency of NF in DWI.

We did not find a significant difference between contralateral occlusion and the occur‐ rence of NF after CAS. This finding confirms the clinical reasoning that patients with carotid stenosis and contralateral carotid occlusion have an embolism risk similar to that of other patients during CAS treatment. This fact contrasts with endarterectomy, for which the clinical results are materially negatively influenced by the presence of contralateral carotid occlusion [10,91-93].

The fluoroscopy time used in CAS may reflect the technical difficulty of the procedure as this time is equivalent to the set of short intervals in which X-ray was applied during the maneuvers necessary for the catheters, guides, balloons, stents, and other materials [82]. Pinheiro et al. [48] used fluoroscopy for 21 min (average) per CAS, a result similar to our series (22.93 min per CAS). As in our study, Tedesco et al. [70] did not find a correlation between long fluoroscopy times or greater amounts of contrast and the appearance of NF after CAS. Conversely, Rapp et al. [77] found an increase in NF after CAS depending on the fluoroscopy time used. However, the fact that we did not find a significant difference in the fluoroscopy time between the groups with and without embolism suggests that cases in which the angioplasty is technically difficult may require longer times for the interven‐ tionist, but theoretically, the increased time does not increase in the risks of embolism. The CASs in this study were always conducted by an individual with a considerable amount of experience. The only way to exclude this bias would be to evaluate the learning curve of a technician in training, which may explain the results of [77].

Although each contrast injection has an unknown theoretical risk of carrying emboligenic particles, this was not proven in our series, but there was not a significant difference in volume between the groups with and without NF. Nonetheless, we remember that, in medical services such as ours with a neuroradiology practice, the cases of embolism are possibly not due to the technique used because the contrast volume and the fluoroscopy time are similar for both groups. Moreover, it is possible that the risk of embolism may be endogenous to patients at a neuroradiology institution where the iatrogenic embolism factor is studied and controlled. The study by Kato et al. [94], as well as ours, did not find a significant difference in the groups with and without NF regarding contrast volume, duration of the procedure, and the use of addi‐ tional catheters.

DWI are found in a substantial number of carotid surgeries (endarterectomy), heart and coronary surgeries, and interventions with cerebral angiographies [63,101,102]. Cardiac

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Willinsky et al. [82] point to mechanisms related to brain catheterization, such as throm‐ boembolism resulting from the withdrawal of the guide within the catheter. The withdrawal causes the empty space of the catheter to fill with blood. This space is subjected to stagnation, unnoticed by the inexperienced practitioner, and causes the formation of emboli [79]. Other mechanisms cited are the dissection and fracture of plaques; the fragmentation of plaques with catheters, guide catheters and guide wires; platelet activation; changes in clotting factors; and

Willinsky et al. [82] published a five-year retrospective study of 2,899 cerebral angiogra‐ phies and found neurological complications in 39 (1.3%), 20 of which were transitory (0.7%), five (0.2%) were reversed, and 14 (0.5%) were permanent. Neurological events in angiogra‐ phy were significantly more frequent in older patients (>55 years) and patients with concomitant cardiovascular disease and when the fluoroscopy was longer [82]. Kaufmann et al. [95] published the widest series of cerebral angiographies that resulted in clinical complications by evaluating 19,827 consecutive patients in a 22-year retrospective study at the Mayo Clinic. They found neurological complications in 2.63% of patients, permanent infarcts in 0.14%, and deaths in 0.06% [95]. Hematoma at the puncture site was the most common occurrence (4.2%). The independent factors identified as associated with neurolog‐ ical complications included atherosclerotic cerebrovascular disease, transient ischemic

Therefore, we assume that there is a theoretical risk of brain embolism, including possible

According to some authors, the diffusion MRI technique is the most efficient tool for detecting

Among the interventional procedures, carotid angioplasty achieved a significant reduction in embolism with the introduction of protection systems, but emboli were not avoided com‐ pletely [35,37,46,68,73]. Good practice in neuroradiology procedures appears to be a mitigating factor for embolic damage during carotid angioplasty procedures. Consistent with our idea, Verzini et al. and Piñero et al. said that the interventionist's experience is a factor for reducing periprocedural complications [68,71,104]. For du Mesnil de Rochemont et al. [46], uninten‐ tional movement of the filter during the intervention is a potential cause of microemboli and mainly occurs during the initial learning curve. This movement can largely be avoided with improved interventional technique and new materials [46,68]. We believe that the learning

Tedesco et al. [70] stated that their CAS program was modified to include the omission of the aortic arch. This change began when MRI images provided sufficient anatomic detail and initiated anticoagulation before the passage of guides and catheters in the ascending and transverse aorta [70]. Thus, these authors state that aortography should be reserved for patients for whom the MRI before CAS does not provide anatomic details to guide the catheter. In

bypass surgery may induce NF for cerebral ischemia in up to 45% of patients [103].

the introduction of air bubbles [36,46].

attacks, and subarachnoid hemorrhage [95].

acute focal brain ischemia [68,71,76].

severe ischemic events, with all of the interventional procedures.

curve for CAS might be long and could exceed 200 cases.

In our series, greater number of angiographies was found in the group that showed NF, and the occurrence of NF varied based on the type of exam applied. Most of the exams defined as broad were associated with emboli, and most of the brief exams did not show any NF after CAS. However, there was no statistical confirmation.

Following the same trend, the average DSA per patient was greater in the patients with NF (average 3.11) than among patients (average 2.78) without NF. Despite the theoretical risk of increasing embolism with the diagnostic exam, the statistical analysis was not sufficient to prove this hypothesis. Thus, the greater the number of vessels on which angiographies were performed, the higher the occurrence of NF. The logical deduction is that conventional angiography has the same responsibility for causing NF as angioplasty alone.

The catheter itself is a potential source of embolism, although complication rates are low [95], and most complications are asymptomatic ischemic complications [61]. Bendszus et al. were the first to publish diffusion MRI as a detection method for clinically silent emboli after cerebral angiographies. They found 42 hypersignal foci in the DWI in 23 out of 100 (23%) patients after DSA with manual injection of the contrast, all without neurological deficits [80].

Britt et al., in a short series, estimated an incidence of less than 9% of asymptomatic cerebral infarcts in diffusion in patients undergoing cerebral angiography for diagnostic purposes [96]. Kato et al. [94], in a study of 50 patients, observed NF in the diffusion after DSA in 8 of the 41 (19.51%) patients. Chuah et al. [97] found NF after angiographies in 3 of 20 (15%) patients, all of which were smaller than 10 mm and occurred at a rate of only one per patient.

Angiography of the aortic arch before CAS was associated with a high risk of microemboli, according to a publication of 27 CASs by Tedesco et al. [70]. This study reports that the aortography by catheter was avoided in cases where ulcers or stenosis were identified in the aortic arch during the revision of exams conducted immediately before CAS. Some authors have reduced the use of aortography by catheter. After the inclusion of MRI angiography in the protocol by Rapp et al. [77], digital angiography by catheter was abolished in 81% of CASs.

In the detailed statistical analysis using logistic regression of our data, we did not find a significant difference between DSA of the aortic arch (p = 0.701) and the appearance of NF in diffusion after CAS. In addition to CAS and DSA, several other catheter techniques show risks of cerebral embolism during the procedure. Rordorf et al. [98] found lesions in diffusion in 8 of 14 (57%) patients after embolization of unruptured cerebral aneurysms. In this series, the majority, with the exception of one new focus, was ipsilateral to the treated aneurysm [98]. Cronqvist et al. [99] published a series of 21 patients suffering from cerebral arteriovenous malformation who underwent 50 embolization procedures. In their study, NF were less frequent (22% of procedures). Of the 35 NF found in DWI, 23 (66%) were of ischemic origin, 8 (23%) represented perinidal venous clots, and 4 (11%) were of uncertain origin [99].

Brain catheterization is not the only cause of brain embolism. In prospective studies, there was an incidence of up to 15% for cerebral NF after cardiac catheterization [100]. Ischemia foci in DWI are found in a substantial number of carotid surgeries (endarterectomy), heart and coronary surgeries, and interventions with cerebral angiographies [63,101,102]. Cardiac bypass surgery may induce NF for cerebral ischemia in up to 45% of patients [103].

study by Kato et al. [94], as well as ours, did not find a significant difference in the groups with and without NF regarding contrast volume, duration of the procedure, and the use of addi‐

In our series, greater number of angiographies was found in the group that showed NF, and the occurrence of NF varied based on the type of exam applied. Most of the exams defined as broad were associated with emboli, and most of the brief exams did not show any NF after

Following the same trend, the average DSA per patient was greater in the patients with NF (average 3.11) than among patients (average 2.78) without NF. Despite the theoretical risk of increasing embolism with the diagnostic exam, the statistical analysis was not sufficient to prove this hypothesis. Thus, the greater the number of vessels on which angiographies were performed, the higher the occurrence of NF. The logical deduction is that conventional

The catheter itself is a potential source of embolism, although complication rates are low [95], and most complications are asymptomatic ischemic complications [61]. Bendszus et al. were the first to publish diffusion MRI as a detection method for clinically silent emboli after cerebral angiographies. They found 42 hypersignal foci in the DWI in 23 out of 100 (23%) patients after

Britt et al., in a short series, estimated an incidence of less than 9% of asymptomatic cerebral infarcts in diffusion in patients undergoing cerebral angiography for diagnostic purposes [96]. Kato et al. [94], in a study of 50 patients, observed NF in the diffusion after DSA in 8 of the 41 (19.51%) patients. Chuah et al. [97] found NF after angiographies in 3 of 20 (15%) patients, all

Angiography of the aortic arch before CAS was associated with a high risk of microemboli, according to a publication of 27 CASs by Tedesco et al. [70]. This study reports that the aortography by catheter was avoided in cases where ulcers or stenosis were identified in the aortic arch during the revision of exams conducted immediately before CAS. Some authors have reduced the use of aortography by catheter. After the inclusion of MRI angiography in the protocol by Rapp et al. [77], digital angiography by catheter was abolished in 81% of CASs. In the detailed statistical analysis using logistic regression of our data, we did not find a significant difference between DSA of the aortic arch (p = 0.701) and the appearance of NF in diffusion after CAS. In addition to CAS and DSA, several other catheter techniques show risks of cerebral embolism during the procedure. Rordorf et al. [98] found lesions in diffusion in 8 of 14 (57%) patients after embolization of unruptured cerebral aneurysms. In this series, the majority, with the exception of one new focus, was ipsilateral to the treated aneurysm [98]. Cronqvist et al. [99] published a series of 21 patients suffering from cerebral arteriovenous malformation who underwent 50 embolization procedures. In their study, NF were less frequent (22% of procedures). Of the 35 NF found in DWI, 23 (66%) were of ischemic origin, 8

angiography has the same responsibility for causing NF as angioplasty alone.

DSA with manual injection of the contrast, all without neurological deficits [80].

of which were smaller than 10 mm and occurred at a rate of only one per patient.

(23%) represented perinidal venous clots, and 4 (11%) were of uncertain origin [99].

Brain catheterization is not the only cause of brain embolism. In prospective studies, there was an incidence of up to 15% for cerebral NF after cardiac catheterization [100]. Ischemia foci in

tional catheters.

CAS. However, there was no statistical confirmation.

184 Carotid Artery Disease - From Bench to Bedside and Beyond

Willinsky et al. [82] point to mechanisms related to brain catheterization, such as throm‐ boembolism resulting from the withdrawal of the guide within the catheter. The withdrawal causes the empty space of the catheter to fill with blood. This space is subjected to stagnation, unnoticed by the inexperienced practitioner, and causes the formation of emboli [79]. Other mechanisms cited are the dissection and fracture of plaques; the fragmentation of plaques with catheters, guide catheters and guide wires; platelet activation; changes in clotting factors; and the introduction of air bubbles [36,46].

Willinsky et al. [82] published a five-year retrospective study of 2,899 cerebral angiogra‐ phies and found neurological complications in 39 (1.3%), 20 of which were transitory (0.7%), five (0.2%) were reversed, and 14 (0.5%) were permanent. Neurological events in angiogra‐ phy were significantly more frequent in older patients (>55 years) and patients with concomitant cardiovascular disease and when the fluoroscopy was longer [82]. Kaufmann et al. [95] published the widest series of cerebral angiographies that resulted in clinical complications by evaluating 19,827 consecutive patients in a 22-year retrospective study at the Mayo Clinic. They found neurological complications in 2.63% of patients, permanent infarcts in 0.14%, and deaths in 0.06% [95]. Hematoma at the puncture site was the most common occurrence (4.2%). The independent factors identified as associated with neurolog‐ ical complications included atherosclerotic cerebrovascular disease, transient ischemic attacks, and subarachnoid hemorrhage [95].

Therefore, we assume that there is a theoretical risk of brain embolism, including possible severe ischemic events, with all of the interventional procedures.

According to some authors, the diffusion MRI technique is the most efficient tool for detecting acute focal brain ischemia [68,71,76].

Among the interventional procedures, carotid angioplasty achieved a significant reduction in embolism with the introduction of protection systems, but emboli were not avoided com‐ pletely [35,37,46,68,73]. Good practice in neuroradiology procedures appears to be a mitigating factor for embolic damage during carotid angioplasty procedures. Consistent with our idea, Verzini et al. and Piñero et al. said that the interventionist's experience is a factor for reducing periprocedural complications [68,71,104]. For du Mesnil de Rochemont et al. [46], uninten‐ tional movement of the filter during the intervention is a potential cause of microemboli and mainly occurs during the initial learning curve. This movement can largely be avoided with improved interventional technique and new materials [46,68]. We believe that the learning curve for CAS might be long and could exceed 200 cases.

Tedesco et al. [70] stated that their CAS program was modified to include the omission of the aortic arch. This change began when MRI images provided sufficient anatomic detail and initiated anticoagulation before the passage of guides and catheters in the ascending and transverse aorta [70]. Thus, these authors state that aortography should be reserved for patients for whom the MRI before CAS does not provide anatomic details to guide the catheter. In contrast, these same authors affirm that more complex and challenging aortic arches (described as Type II and Type III) were not identified as high risk for embolization [70]. Most authors describe rates of non-symptomatic NF in DWI in the area contralateral to CAS that are similar to brain angiography rates.

regarding neurological complications and death up to 30 days after CAS. Additionally, du Mesnil de Rochemont et al. [46] found a tendency for a greater number of ischemic lesions with the use of segmented nitinol stents (open cells) compared to Wallstent®. They suggested that open-cell stents are used in more technically complex cases with marked vascular tortuosity. In our study, we obtained the same result, but the types of stents were used without differentiation regarding tortuosity. A prospective study by Sahin at al. analyzing patients with closed-cell and open-cell stents showed that open-cell stents were less associated with clinical events of brain ischemia [106]. Moreover, Hart et al. [45], studying 701 CASs, stated that closed-cell stents and eccentric filters had lower rates of TIA/ICVA/death combination 30 days after the procedure in symptomatic patients and patients with echolucent plaques in ultrasound. Our results and from other authors led to the theory that these stent and filter designs may be intrinsically more effective at preventing brain embolism from fractured

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The retrospective analysis of 3,179 consecutive CASs by Bosiers et al. [107] showed a significant difference with a greater rate of neurological complications (symptomatic or not) with opencell stents. Using DWI specifically to study NF after CAS, the recent meta-analysis from Schnaudigel et al. [37] shows that the incidence of NF after CAS was significantly greater in open-cell stents than in closed-cell stents. Thus, our study is in agreement with those of other authors [32,37] and supports the idea that closed-cell stents are sufficient to cover plaque and prevent the embolization of large plaque particles post-CAS through the struts of the stent.

Several studies with separated groups with and without cerebral protection support the effectiveness of protection systems [34,35,37]. Kastrup et al. [33] found a combined frequency of CVA and death after 30 days of 1.8% for the group with protection and 5.5% for the group without protection (p<0.001). Additionally, a lower incidence of serious neurological compli‐ cations was found when a filter was used (2.2%) than without a filter (5.5%) [38]. By studying groups with and without protection and the relationship with NF formation, Kastrup et al. found emboli in 49% of patients with cerebral protection and 67% of patients without protec‐ tion [34]. Two years later, this group updated their data and published the occurrence of NF

As expected, the meta-analysis by Schnaudigel et al. [37] found a lower index of foci ipsilateral to the CAS in DWI in patients with the use of cerebral protection systems (33%) than in patients without the use of protection (45%). The same authors cited no change in the risk of NF occurrence in the contralateral area with or without cerebral protection (respectively, 14% and 13%; p=0.6) [37]. In our study, all cases were performed with a protection filter. The use of a control group without a filter would be considered unethical according to our research group. However, different types of filters were compared, and the technique used to place the guide

In addition to innovation of materials, proper training is needed for each type of filter. Attention to the correct apposition of the filter device should be a mandatory stage in the CAS [108], as it requires experience in executing the procedure because of the natural tortuosity of carotids. Positioning can be hampered by vascular tortuosity, which is sometimes excessive.

after CAS without a filter in 68% of patients and 52% of patients with a filter [35].

plaque or other thrombogenic material.

catheter was analyzed.

The initial catheterization of CAS cannot be excluded because the procedures cannot be separated. Although the catheterization occurs alone for diagnostic purposes [80], angiogra‐ phy is a mandatory initial stage for all angioplasties [36]. Bendszus et al. [105] subsequently published that the use of heparin and air filters materially reduced ischemic events in brain catheterization.

Most studies on the relationship between NF in DWI and CAS only mention the material used; few describe a single access technique for the common carotid artery, usually direct access. In all cases, we used a standardized form for the highest-caliber (8 Fr) guide catheter, believing that the good stabilization of the system achieved by this material facilitates the manipulation of materials (filter, stent, balloons).

In our experience, direct access without exchanges is preferable only in technically simple cases with favorable anatomy. According to our review, our study is the only one that comparatively analyzes the catheterization access technique with the guide catheter in the carotid artery undergoing angioplasty. The risk for each technique to be involved with embolism was 50.00%, 50.00%, 63.64%, and 25.00%, respectively, for direct access, exchange in the external carotid artery, exchange in the common carotid artery, and triaxial. Thus, the triaxial technique showed a tendency for greater safety, possibly by having a more gradual progression of size (from the guide wire to the guide catheter) and causing less aggravation of the aortic arch and supra-aortic trunks. We can add that the triaxial technique should be used as a first attempt when technically possible.

Because the triaxial form of access showed a small number of NF, although without statistical significance, it is possible to predict that replacing the set (a short-valved introducer and guide catheter) with a long sheath (110 cm), which is currently available, in a single product that is also used triaxially (introducer, sheath, and guide) may reduce the index of embolic compli‐ cations. More comparative studies of compatible techniques (guide, catheter, sheath) and other techniques are needed to prove this trend.

Although the filter is the central focus of discussion in most articles cited here for preventing embolization during CAS, the stent is the material used to effectively treat plaque to prevent embolic ischemic conditions in the long run. Our data do not show important significant differences between the brands of stent tested and the brands of protection filters used, as in Kastrup et al. [35] and Palombo et al. [75]. However, it is possible to identify a tendency for a smaller number of NF with a closed-cell stent (Wallstent®) compared with the open-cell stents. The Protégé® stent showed a reasonable resolve for the appearance of NF ipsilateral to CAS, but the small number of times this material was used precludes reliable statements about this relationship.

Schillinger et al. [30], studying the impact of open-cell versus closed-cell stents, reviewed data from 10 European centers totaling 1,684 patients and did not identify a significant difference regarding neurological complications and death up to 30 days after CAS. Additionally, du Mesnil de Rochemont et al. [46] found a tendency for a greater number of ischemic lesions with the use of segmented nitinol stents (open cells) compared to Wallstent®. They suggested that open-cell stents are used in more technically complex cases with marked vascular tortuosity. In our study, we obtained the same result, but the types of stents were used without differentiation regarding tortuosity. A prospective study by Sahin at al. analyzing patients with closed-cell and open-cell stents showed that open-cell stents were less associated with clinical events of brain ischemia [106]. Moreover, Hart et al. [45], studying 701 CASs, stated that closed-cell stents and eccentric filters had lower rates of TIA/ICVA/death combination 30 days after the procedure in symptomatic patients and patients with echolucent plaques in ultrasound. Our results and from other authors led to the theory that these stent and filter designs may be intrinsically more effective at preventing brain embolism from fractured plaque or other thrombogenic material.

contrast, these same authors affirm that more complex and challenging aortic arches (described as Type II and Type III) were not identified as high risk for embolization [70]. Most authors describe rates of non-symptomatic NF in DWI in the area contralateral to CAS that are similar

The initial catheterization of CAS cannot be excluded because the procedures cannot be separated. Although the catheterization occurs alone for diagnostic purposes [80], angiogra‐ phy is a mandatory initial stage for all angioplasties [36]. Bendszus et al. [105] subsequently published that the use of heparin and air filters materially reduced ischemic events in brain

Most studies on the relationship between NF in DWI and CAS only mention the material used; few describe a single access technique for the common carotid artery, usually direct access. In all cases, we used a standardized form for the highest-caliber (8 Fr) guide catheter, believing that the good stabilization of the system achieved by this material facilitates the manipulation

In our experience, direct access without exchanges is preferable only in technically simple cases with favorable anatomy. According to our review, our study is the only one that comparatively analyzes the catheterization access technique with the guide catheter in the carotid artery undergoing angioplasty. The risk for each technique to be involved with embolism was 50.00%, 50.00%, 63.64%, and 25.00%, respectively, for direct access, exchange in the external carotid artery, exchange in the common carotid artery, and triaxial. Thus, the triaxial technique showed a tendency for greater safety, possibly by having a more gradual progression of size (from the guide wire to the guide catheter) and causing less aggravation of the aortic arch and supra-aortic trunks. We can add that the triaxial technique should be used as a first attempt

Because the triaxial form of access showed a small number of NF, although without statistical significance, it is possible to predict that replacing the set (a short-valved introducer and guide catheter) with a long sheath (110 cm), which is currently available, in a single product that is also used triaxially (introducer, sheath, and guide) may reduce the index of embolic compli‐ cations. More comparative studies of compatible techniques (guide, catheter, sheath) and other

Although the filter is the central focus of discussion in most articles cited here for preventing embolization during CAS, the stent is the material used to effectively treat plaque to prevent embolic ischemic conditions in the long run. Our data do not show important significant differences between the brands of stent tested and the brands of protection filters used, as in Kastrup et al. [35] and Palombo et al. [75]. However, it is possible to identify a tendency for a smaller number of NF with a closed-cell stent (Wallstent®) compared with the open-cell stents. The Protégé® stent showed a reasonable resolve for the appearance of NF ipsilateral to CAS, but the small number of times this material was used precludes reliable statements about this

Schillinger et al. [30], studying the impact of open-cell versus closed-cell stents, reviewed data from 10 European centers totaling 1,684 patients and did not identify a significant difference

to brain angiography rates.

186 Carotid Artery Disease - From Bench to Bedside and Beyond

of materials (filter, stent, balloons).

when technically possible.

relationship.

techniques are needed to prove this trend.

catheterization.

The retrospective analysis of 3,179 consecutive CASs by Bosiers et al. [107] showed a significant difference with a greater rate of neurological complications (symptomatic or not) with opencell stents. Using DWI specifically to study NF after CAS, the recent meta-analysis from Schnaudigel et al. [37] shows that the incidence of NF after CAS was significantly greater in open-cell stents than in closed-cell stents. Thus, our study is in agreement with those of other authors [32,37] and supports the idea that closed-cell stents are sufficient to cover plaque and prevent the embolization of large plaque particles post-CAS through the struts of the stent.

Several studies with separated groups with and without cerebral protection support the effectiveness of protection systems [34,35,37]. Kastrup et al. [33] found a combined frequency of CVA and death after 30 days of 1.8% for the group with protection and 5.5% for the group without protection (p<0.001). Additionally, a lower incidence of serious neurological compli‐ cations was found when a filter was used (2.2%) than without a filter (5.5%) [38]. By studying groups with and without protection and the relationship with NF formation, Kastrup et al. found emboli in 49% of patients with cerebral protection and 67% of patients without protec‐ tion [34]. Two years later, this group updated their data and published the occurrence of NF after CAS without a filter in 68% of patients and 52% of patients with a filter [35].

As expected, the meta-analysis by Schnaudigel et al. [37] found a lower index of foci ipsilateral to the CAS in DWI in patients with the use of cerebral protection systems (33%) than in patients without the use of protection (45%). The same authors cited no change in the risk of NF occurrence in the contralateral area with or without cerebral protection (respectively, 14% and 13%; p=0.6) [37]. In our study, all cases were performed with a protection filter. The use of a control group without a filter would be considered unethical according to our research group. However, different types of filters were compared, and the technique used to place the guide catheter was analyzed.

In addition to innovation of materials, proper training is needed for each type of filter. Attention to the correct apposition of the filter device should be a mandatory stage in the CAS [108], as it requires experience in executing the procedure because of the natural tortuosity of carotids. Positioning can be hampered by vascular tortuosity, which is sometimes excessive. The choice of filter is also important because, if it has a smaller diameter than the vessel, blood and particles pass between the filter and the artery wall [46,104,109].

flow predisposes the fragmentation of content retained in the filter. Physician experience and speed are necessary to reduce the time of the procedure and avoid this fragmentation and

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The filters that were used in the protocol of this study had mesh with pores from 100 to 140 µm, reducing the migration of cholesterol crystals and clots, platelet aggregations, and macrofragments of atheromatous plaques through filtering. The diameter of the filter pores used was smaller than the particles described by Theron et al. [114] and Ohki et al. [90] and

Our series showed an average of 1.6 NF per patient, a number well below the average of 33 particles found adhered to filters in the study by Angelini et al. [50]. It is possible that filters provide real protection, given the disparity between these numbers. Nonetheless, the action of each individual's thrombolysis system cannot be excluded as also drastically, or at least

The disparity between the low number of ischemic events after CAS [33,38] and the relatively high frequency of multiple small restriction foci in diffusion after CAS [35,69,70,73] that are compatible with embolism suggests that filters mainly act by retaining large particles that could evolve into clinical conditions of ischemia, rather than by grasping small particles. In our series, the eccentric filter EPI® had embolism in diffusion in 44% of cases, suggesting apparently superior protection compared to other models. The Angioguard® filter contained emboli in 50% of cases, while the Emboshield® device showed the highest rate of emboli (71.43%) in the group. Our data establish a strong tendency for superior protection measured in the eccentric filter (0.958 NF ipsilateral) compared to the concentric designs (2.100 NF ipsilateral). A study from Tedesco et al. [70] found a high rate of NF (70% of patients). These authors used a combination of the concentric filter and the open-cell stent, which may have contributed to the high rate of emboli. While there may be unequal protection between these filters, the difference shown in this series is not statistically significant. Our data cannot completely indicate greater protection of the eccentric model compared to the concentric model. Furthermore, poor distribution among types of filters with very small groups (Angio‐ guard®, n=4) was observed. Thus, we avoid speculative comparison regarding the safety of

A retrospective study of 3,160 CAS published Iyer et al. [115] found that the type of protection (nine different systems, including concentric and eccentric filters and proximal and distal occlusion balloons) had no influence on the clinical result. However, these authors did not

For Piñero et al. [48,111], the difficulty of correctly positioning the filter on the wall of tortuous vessels, the displacement of material during the release, the creation of emboli by the relatively high-profile crossover and low flexibility, the loss of accumulated particles during the removal of the filter, and the diameter of the filter's pores appear to be very important to the appearance of ischemia related to embolization. This finding should lead to future studies that help to

potential emboli between the pores [68].

each device.

study the brain using MRI after CAS.

perfect protection systems [48,111].

than most of the particles described by Angelini et al. [50].

partially, reducing the permanence of emboli at its distal point.

Two articles from Müller-Hulsbeck et al. [47,57] using an animal model of the carotid artery showed that miniscule particles of debris smaller than 100 µm can pass the pores of the filters [57]. Additionally, the filters can damage the vessel walls [47], which may subsequently result in the displacement of fragments and thrombi due to accidental movement of the filtering device. Other authors claim that we cannot exclude the possibility that when the filters are closed and removed, the collection system may swing the tool and loosen some of the captured particles, freeing them in the vessel lumen [46,68].

It is possible that because the stent and balloon use a microguide for the devices, in the case of the EPI/EZ® and Angioguard® filters used in this study, they may mobilize the filter and release free particles. The Emboshield® device does not carry this theoretical risk because it stays no fixed to the guide while it is in action. However, in our study, the Emboshield® device has an average appearance of NF similar to the other concentric device, Angioguard®, and both have a higher average than the eccentric device EPI®. This result reflects the need for training with each device because the only way of preventing the displacement of materials is the correct use of the devices.

In 2000, Coggia et al. [110] published the passage of particles in all stages of CAS in an ex vivo study. Most of the particles were smaller than 60 µm, and the pores of the commercially available filters were approximately 100 µm. The passage of these particles through the protection devices and entrapment in capillaries or cerebral arteries is possible [110]. Angelini et al. [50] showed through electronic microscopy that 83.7% of filters have particles adhered to them and, on average, the filters contained 33.7 particles (24 to 46). In that study, the average diameter of the fragments captured in the filters was 289.5 µm (1.08 to 5043.5 µm). The main particles found by this group were soft acellular material, lipid-laden macrophages, and cholesterol clefts. Less frequently, they found calcium particles and platelet aggregates. All of these materials are typically identified in atherosclerotic plaques, whether they are compli‐ cated or not. When a protective balloon was used, similar materials were found [50].

In 2009, Piñero et al. [111] published a structural analysis of the material contained in filters after angioplasties and stated that atherosclerotic plaques and vessel walls are the main sources of microemboli during CAS [71,111]. However, a study on the action of cerebral protection devices found that 88% of particles were retained in the filters in an ex vivo simulation of CAS [112]. Piñero et al. [48,71,111] considered filter diameter to be very important but not the only factor in the formation of NF. They claimed that bad positioning of the filter on the carotid wall due to tortuosity, displacement of the filter while handling the materials, and high profile crossover are technical difficulties that await future studies and improvements in materials. Rough handling can promote the formation of emboli during the positioning and removal of the filter.

Some authors explain that the size of debris removed from the filters differs from the real size at the moment of embolization and that most of the small emboli may be the result of the fragmentation of particles trying to pass through the grid of the filter [113]. Thus, continuous flow predisposes the fragmentation of content retained in the filter. Physician experience and speed are necessary to reduce the time of the procedure and avoid this fragmentation and potential emboli between the pores [68].

The choice of filter is also important because, if it has a smaller diameter than the vessel, blood

Two articles from Müller-Hulsbeck et al. [47,57] using an animal model of the carotid artery showed that miniscule particles of debris smaller than 100 µm can pass the pores of the filters [57]. Additionally, the filters can damage the vessel walls [47], which may subsequently result in the displacement of fragments and thrombi due to accidental movement of the filtering device. Other authors claim that we cannot exclude the possibility that when the filters are closed and removed, the collection system may swing the tool and loosen some of the captured

It is possible that because the stent and balloon use a microguide for the devices, in the case of the EPI/EZ® and Angioguard® filters used in this study, they may mobilize the filter and release free particles. The Emboshield® device does not carry this theoretical risk because it stays no fixed to the guide while it is in action. However, in our study, the Emboshield® device has an average appearance of NF similar to the other concentric device, Angioguard®, and both have a higher average than the eccentric device EPI®. This result reflects the need for training with each device because the only way of preventing the displacement of materials is

In 2000, Coggia et al. [110] published the passage of particles in all stages of CAS in an ex vivo study. Most of the particles were smaller than 60 µm, and the pores of the commercially available filters were approximately 100 µm. The passage of these particles through the protection devices and entrapment in capillaries or cerebral arteries is possible [110]. Angelini et al. [50] showed through electronic microscopy that 83.7% of filters have particles adhered to them and, on average, the filters contained 33.7 particles (24 to 46). In that study, the average diameter of the fragments captured in the filters was 289.5 µm (1.08 to 5043.5 µm). The main particles found by this group were soft acellular material, lipid-laden macrophages, and cholesterol clefts. Less frequently, they found calcium particles and platelet aggregates. All of these materials are typically identified in atherosclerotic plaques, whether they are compli‐

cated or not. When a protective balloon was used, similar materials were found [50].

In 2009, Piñero et al. [111] published a structural analysis of the material contained in filters after angioplasties and stated that atherosclerotic plaques and vessel walls are the main sources of microemboli during CAS [71,111]. However, a study on the action of cerebral protection devices found that 88% of particles were retained in the filters in an ex vivo simulation of CAS [112]. Piñero et al. [48,71,111] considered filter diameter to be very important but not the only factor in the formation of NF. They claimed that bad positioning of the filter on the carotid wall due to tortuosity, displacement of the filter while handling the materials, and high profile crossover are technical difficulties that await future studies and improvements in materials. Rough handling can promote the formation of emboli during the positioning and removal of

Some authors explain that the size of debris removed from the filters differs from the real size at the moment of embolization and that most of the small emboli may be the result of the fragmentation of particles trying to pass through the grid of the filter [113]. Thus, continuous

and particles pass between the filter and the artery wall [46,104,109].

particles, freeing them in the vessel lumen [46,68].

188 Carotid Artery Disease - From Bench to Bedside and Beyond

the correct use of the devices.

the filter.

The filters that were used in the protocol of this study had mesh with pores from 100 to 140 µm, reducing the migration of cholesterol crystals and clots, platelet aggregations, and macrofragments of atheromatous plaques through filtering. The diameter of the filter pores used was smaller than the particles described by Theron et al. [114] and Ohki et al. [90] and than most of the particles described by Angelini et al. [50].

Our series showed an average of 1.6 NF per patient, a number well below the average of 33 particles found adhered to filters in the study by Angelini et al. [50]. It is possible that filters provide real protection, given the disparity between these numbers. Nonetheless, the action of each individual's thrombolysis system cannot be excluded as also drastically, or at least partially, reducing the permanence of emboli at its distal point.

The disparity between the low number of ischemic events after CAS [33,38] and the relatively high frequency of multiple small restriction foci in diffusion after CAS [35,69,70,73] that are compatible with embolism suggests that filters mainly act by retaining large particles that could evolve into clinical conditions of ischemia, rather than by grasping small particles. In our series, the eccentric filter EPI® had embolism in diffusion in 44% of cases, suggesting apparently superior protection compared to other models. The Angioguard® filter contained emboli in 50% of cases, while the Emboshield® device showed the highest rate of emboli (71.43%) in the group. Our data establish a strong tendency for superior protection measured in the eccentric filter (0.958 NF ipsilateral) compared to the concentric designs (2.100 NF ipsilateral). A study from Tedesco et al. [70] found a high rate of NF (70% of patients). These authors used a combination of the concentric filter and the open-cell stent, which may have contributed to the high rate of emboli. While there may be unequal protection between these filters, the difference shown in this series is not statistically significant. Our data cannot completely indicate greater protection of the eccentric model compared to the concentric model. Furthermore, poor distribution among types of filters with very small groups (Angio‐ guard®, n=4) was observed. Thus, we avoid speculative comparison regarding the safety of each device.

A retrospective study of 3,160 CAS published Iyer et al. [115] found that the type of protection (nine different systems, including concentric and eccentric filters and proximal and distal occlusion balloons) had no influence on the clinical result. However, these authors did not study the brain using MRI after CAS.

For Piñero et al. [48,111], the difficulty of correctly positioning the filter on the wall of tortuous vessels, the displacement of material during the release, the creation of emboli by the relatively high-profile crossover and low flexibility, the loss of accumulated particles during the removal of the filter, and the diameter of the filter's pores appear to be very important to the appearance of ischemia related to embolization. This finding should lead to future studies that help to perfect protection systems [48,111].

In 2006, du Mesnil de Rochemont et al. [46] found three (6%) occlusions of filters by debris or clots in a series of 50 CASs. In a series of 162 CASs, Piñero et al. found filter occlusion in four (2.5%) patients during the procedure [48]. It is predicted that these cases will become significant infarcts due to the large size of the particles because it was sufficient to obstruct the filter pores up to total occlusion of the flow. Piñero et al. [48] assume that, without the use of a filter in these cases, the morbidity of their series would increase from 4 to 6.5%.

clopidogrel was significantly higher in patients with foci of microemboli in DWI after CAS than in patients without foci of microemboli in MRI after CAS. In their series, all the patients

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A randomized prospective study evaluated platelet activation after coronary stents in pigs and showed that the closed-cell stent produced less intimal prolapse and thus a smoother stentvessel wall interface than the stent with open-cells and that platelet activation was greater during the 30 days following implantation of an open-cell versus a closed-cell stent [122].

Our study concentrates on the designs of stents and filters, but other particularities of con‐ structing the materials can interfere in the safety of CAS, such as the type of filtering element. A study considered that perforated membrane filters have greater resistance to cerebral blood flow [123], but it did not evaluate whether there was greater capture of emboli. Our study also had a relatively short follow-up time. We only used the period when the patients were hospitalized, generally three to four days. We consider that this peri-procedure period is sufficient to evaluate the late appearance of NF because the disappearance of NF is described

The use of protection systems aims to avoid massive embolism, which occasionally happens. However, a perfect cerebral protection system is not commercially available. While cerebral protection with filters is effective, it is necessary to develop new protection devices that are more effective and can be occlusive systems with a lower profile and greater ease of use. Both techniques, angioplasty with stent (with filter or flow occlusion systems) and endarterectomy,

New restriction foci (NF) in diffusion were present in half of the patients after CAS with cerebral protection and were most frequently located in the ipsilateral area (77.19%), suggest‐ ing that the filters did not prevent all microemboli. New restriction foci in DWI after CAS were located in regions (22.81%) different than in the angioplasty and were associated with diagnostic catheterization. Therefore, long neurointerventionist medical training should be

The NF in DWI after CAS were mostly small in diameter (<10 mm in 91.53%) and were always

The presence of cerebral infarcts in the T2 sequence in the initial MRI was the only factor that significantly predisposed the appearance of new restriction foci in DWI after CAS. Thus, the risk of microemboli was directly related to intrinsic factors of the patient. Other demographic factors and aspects related to the angioplasty technique were not statistically significant to the occurrence of NF in our study. There was a tendency for other factors, such as the triaxial access technique, asymptomatic patients, and an eccentric filter, to be involved in the appearance of

are involved in cases of intracranial embolism per treatment.

required before CASs are performed.

clinically silent (100%) in our study.

a smaller number of NF after CAS.

who showed clinical ischemic events had resistance to antiplatelets [76].

in some cases [60,68,75].

**14. Conclusions**

There was no case of filter occlusion by debris or thrombi in our series. Vasospasms related to the filtering devices were short-lived and without hemodynamic impairment. Other compli‐ cations related to the filters were not found in this series. Filter occlusion leading to a stopped flow is a rare occurrence. It was more observed with the use of the first generation of EPI® filters, where the diameters of the pores were only 80 µm [46,116].

While the first step in CAS, which includes catheterization, the positioning of the guide catheter and the passage of the filter over the stenosis, occurs without protection, the phases with the greatest number of emboli released from plaque are the implantation of the stent and the angioplasty by balloon. An overload of the filter protection system is the angioplasty by balloon. Piñero at al. [111] showed that the more balloon dilations are applied to CAS, the greater the load of emboli found in the filters. Therefore, physician experience is necessary to use the balloon as delicately as possible.

Unfortunately, the other technique currently used in the treatment of carotid stenosis – CEA – also has ischemic complications [59] and more brain emboli than CAS [37,83]. Another common complication in CEA is lesions to the cranial nerves and cardiac infarction [117,118].

Comparative studies between CEA and CAS found a greater number of NF after CAS than after CEA. However, the lesions in the DWI after CAS are significantly smaller than after the endarterectomy. Analyzing the NF in the DWI after CAS and endarterectomy, Roh et al. [78] reasoned that the lesions in diffusion after CAS are generally asymptomatic and that the lesions in DWI associated with symptoms are more frequent in CEA [37,78]. In recent years, the materials used in CAS have been improved to reduce complications. DWI can be used as a tool in this evolving analysis of materials and also in the technical improvement of neurointervention.

Our study shows some limitations. Data collection of a control group without the use of cerebral protection to prove the device's effectiveness is incorrect based on our ethical views of the procedure, but it is a limitation of the study. However, other published studies that conducted CAS with and without protection systems clearly show a smaller number of NF [35,37] and lower risk of ischemic events [33,38] after CAS in the groups where the devices were used.

The formation of emboli can be impeded by antiplatelet and anticoagulant medications [76], but this is not the focus of our research shown here. In neuroradiology procedures, the prevalence of resistance to aspirin varied from 2 to 21%, and resistance to clopidogrel varied from 43 to 52% [119-121]. This result is extremely important because atheromatous plaques and superimposed thrombi are the main source of microemboli during CAS. A recent study from Song et al. [76] using the VerifyNow system showed that the frequency of resistance to clopidogrel was significantly higher in patients with foci of microemboli in DWI after CAS than in patients without foci of microemboli in MRI after CAS. In their series, all the patients who showed clinical ischemic events had resistance to antiplatelets [76].

A randomized prospective study evaluated platelet activation after coronary stents in pigs and showed that the closed-cell stent produced less intimal prolapse and thus a smoother stentvessel wall interface than the stent with open-cells and that platelet activation was greater during the 30 days following implantation of an open-cell versus a closed-cell stent [122].

Our study concentrates on the designs of stents and filters, but other particularities of con‐ structing the materials can interfere in the safety of CAS, such as the type of filtering element. A study considered that perforated membrane filters have greater resistance to cerebral blood flow [123], but it did not evaluate whether there was greater capture of emboli. Our study also had a relatively short follow-up time. We only used the period when the patients were hospitalized, generally three to four days. We consider that this peri-procedure period is sufficient to evaluate the late appearance of NF because the disappearance of NF is described in some cases [60,68,75].
